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Description of key information

A NOAEL of 16 mg/ kg bw x d and a LOAEL of 80 mg/ kg bw x d were derived for systemic toxicity in a 28-days toxicity study with oral application. Major effects were toxicity of the hematological system.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
16 mg/kg bw/day

Additional information

In a 28-day oral study according to OECD guideline 407 conducted in male and female Wistar rats (5 animals per sex per dose; dailyapplication of 0, 16, 80 or 400 mg o-anisidine/kg bw via gavage), no substance-related (i.e.unspecific) effects were observed at a dose level of 16 mg/(kg bw x d). In animals dosed with 80 mg/kg bw, yellow urine and a slight haemolytic anemia were noted. These effects were more pronounced at400 mg/kg bw. Bilirubin levels in blood and relative liver weights of female animals wereincreased. In both sexes, there were morphological changes of thespleen (haemosiderosis, hyperaemia, and increased extramedullary haematopoiesis) as well as increased erythrocyte formation in the bone marrow (nevertheless no methemoglobin formation was observed) evident within the histopathological examinations made. The high dose group (400 mg/kg)showed salivation, squatting and inflated abdomen at day 15. Reduced body weights andan increase in relative liver and kidney weights was seen in male animals, while in females the glutamic pyruvictransaminase (GPT) levels were increased.Increase of drinking waterconsumption, bilirubin and urea-nitrogen levels in blood, as well as increased relativespleen weights were obviuos in animals of both sexes. From this study, a NO(A)EL of 16 mg/(kg bw x d) and a LOAELof 80 mg/(kg bw x d) was derived.

In another study F344 rats and B6C3F1 mice were subjected to an oral range finding study for o-anisidine hydrochloride (CAS no. 123 -29 -2). The conditions used were as follows: application of 0 - 1,000 - 3,000 -10,000 or 30,000 ppm o-anisidine hydrochloride for 7 weeks via diet to 5 animals/sex/dose (applied doses corresponding to the following body doses in rats: ca. 75, 225, 750 or 2,250 mg/kg bw and day; and in mice: ca. 150, 450, 1,500 or 4,500 mg/kg bw and day).

The results are summarized in the RAR in such a way: doses, which are greater or equal "10,000 ppm in rats resulted in dose-dependent weight depression of more than 10% and moderately enlarged spleens, which were black and granular; spleens of male rats administered 1,000 or 3,000 ppm were granular. In mice doses of (> or equal) 3,000 ppm resulted in dose-dependent weight depression of more than 10%; at doses of (> or equal)10,000 ppm the spleens were also black and enlarged (NCI, 1978)."

Furthermore, the effects seen in the main 2 year-study performed by the NCI (1978) are described too. F344 rats fed with doses of 0, 5000 or 10000 ppm of o-anisidine hydrochloride were killed at 103 -107 weeks and for all animals (the ones found dead as well as the ones sacrificed in the end) histopathological examinations were performed. There was a dose-related depression of body weight noted, but all the non-neoplastic lesions found in histopathology were considered to be not compound related.

In mice the applied doses were 0, 2500 or 5000 ppm and the surviving animals were killed at weeks 104 or 105 of the bioassay. Effects observed are the same as for rats (see above).

There are no studies available concerning repeated inhalation or dermal exposure in experimental animals.

Repeated dose toxicity: via oral route - systemic effects (target organ) cardiovascular / hematological: hematopoiesis; cardiovascular / hematological: spleen

Justification for classification or non-classification

On the basis of the observed haematotoxicity including changes of haematological parameters and morphological effects in corresponding organs (hemosiderin deposition in spleen), at a dose level of 400 mg/kg bw and less pronounced at a dose level of 80 mg/kg bw a classification as STOT re category 2 might be appropriate. But in view of the existing classification which guaranties a high protection level an additional classification as STOT re category 2 seems dispensable.